Phase IIb Randomized Double‑Blind Placebo‑Controlled Study of Eplontersen Plus ALXN2220 Versus Eplontersen + Placebo in Adults with Transthyretin‑Mediated Amyloid Cardiomyopathy

The primary objective is to assess the impact of combined eplontersen and ALXN2220 versus eplontersen plus placebo on functional capacity as measured by the change in cardiopulmonary exercise test peak oxygen consumption (VO2) over 52 weeks in adults with Transthyretin‑Mediated Amyloid Cardiomyopathy (ATTR‑CM). This endpoint reflects exercise tolerance and correlates with disease progression.

Secondary objectives include:

• Evaluation of the effect on cardiac amyloid burden, quantified by extracellular volume (ECV) on cardiac magnetic resonance imaging at 52 weeks.
• Assessment of change in N‑terminal pro B‑type natriuretic peptide (NT‑proBNP) over the same period.
• Measurement of health status using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ‑CSS) at 52 weeks.

The trial enrolled 168 participants diagnosed with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM). Eligible individuals were aged 18 to 85 years, inclusive, and comprised both male and female patients. All subjects met criteria for NYHA functional class I–III, demonstrated elevated NT‑proBNP, and were capable of completing a symptom‑limited maximal cardiopulmonary exercise test at screening. Participants were required to be receiving guideline‑directed, optimized heart‑failure therapy that had been stable for at least four weeks (excluding diuretics) and to have a life expectancy of at least one year as judged by the investigator. Inclusion mandated the ability to provide informed consent and a willingness to adhere to daily self‑administered vitamin A supplementation (3000 IU). The cohort excluded vulnerable populations not meeting these clinical or functional requirements.

The study is a Phase IIb, multicentre, randomized, double‑blind, placebo‑controlled trial evaluating the efficacy and safety of concomitant eplontersen (subcutaneous 45 mg solution) and ALXN2220 (intravenous monoclonal antibody) versus eplontersen with placebo in adult participants with Transthyretin‑Mediated Amyloid Cardiomyopathy. Participants are screened, then randomized 1:1 to one of the two treatment arms and followed for 52 weeks; the overall trial period spans from September 2026 to February 2029. Study visits include:

• Screening visit – confirmation of eligibility, baseline cardiopulmonary exercise test (CPET), NT‑proBNP, and safety labs.
• Baseline/randomization visit – first dose administration and initiation of daily vitamin A supplementation.
• Follow‑up visits (approximately weeks 4, 12, 24, 36, 48) – assessment of adverse events, laboratory parameters, CPET (as scheduled), and patient‑reported outcomes (KCCQ‑CSS).
• End‑of‑study visit at week 52 – final efficacy evaluations, including change in CPET peak VO₂ (primary endpoint), NT‑proBNP, extracellular volume (ECV) subgroup analysis, and safety assessments.

The investigational product eplontersen is supplied as Wainzua 45 mg solution for injection in a pre‑filled pen. The formulation is a sterile solution for subcutaneous use. Participants receive a single 45 mg dose administered subcutaneously at each scheduled visit, with dosing occurring every 4 weeks throughout the 52‑week treatment period. Administration is performed by qualified study personnel, and injection sites are inspected for local reactions. Compliance with the dosing schedule is monitored by review of dosing logs and verification of pen usage records at each study visit.

The second investigational agent, ALXN2220, is a recombinant human anti‑ATTR immunoglobulin G1 monoclonal antibody provided as a solution for intravenous infusion. The product is administered intravenously at the dose and infusion rate defined in the protocol, repeated every 4 weeks in conjunction with eplontersen for the duration of the study. Infusion parameters, including start and end times, are recorded, and participants are observed for infusion‑related adverse events. Adherence to the infusion schedule is tracked through infusion documentation and electronic case report forms.

The control arm utilizes a matching placebo for ALXN2220. The placebo is presented in the same container and appearance as the active monoclonal antibody and is administered intravenously on the same schedule (every 4 weeks) as the active comparator. Blinding is maintained by identical infusion procedures, and compliance is documented in the same manner as for the active treatment.

Efficacy will be evaluated by measuring the change from baseline in CPET peak VO₂ over a 52‑week treatment period. Participants will undergo a cardiopulmonary exercise test at screening to establish baseline values, with a repeat assessment at week 52. The difference between the two time points will constitute the primary efficacy parameter.

Secondary efficacy parameters include the change from baseline in ECV (evaluated in a predefined subgroup), the change from baseline in NT‑proBNP levels, and the change from baseline in the KCCQ‑CSS score. Baseline measurements for each secondary endpoint will be obtained prior to randomisation, with follow‑up assessments performed at week 52. Cardiac magnetic resonance imaging will be used to determine ECV, standard laboratory assays will quantify NT‑proBNP, and the Kansas City Cardiomyopathy Questionnaire will capture the KCCQ‑CSS. All efficacy data will be analysed using change‑from‑baseline comparisons between the eplontersen + ALXN2220 arm and the eplontersen + placebo arm.